These results are supplied for informational purposes only.

Prescribing decisions should be made based on the approved package insert in the country of prescription.

Sponsor / Company: Sanofi Study Identifiers: NCT01673737, UTN U1111-1129-2696

Drug substance(s): SAR260301 Study code: TCD12739
Title of the study: A Phase I/Ib study for the evaluation of SAR260301, administered orally in monotherapy in patients with
advanced solid tumors or lymphomas, and in combination with vemurafenib in patients with
unresectable/metastatic BRAF mutated melanoma
Study center(s): 1 site in Canada and 3 sites in the US
Study period:
Date first patient enrolled: 07/Aug/2012
Date last patient completed: 02/Feb/2015
Phase of development: Phase 1/1b
Objectives:
Primary
Part A

 To determine the maximum tolerated dose (MTD) of SAR260301 administered as monotherapy and either on a once
daily (QD) or twice daily (BID) schedule, to patients with advanced solid tumors or lymphomas.
Part B

 To determine the MTD of SAR260301 administered in combination with the recommended standard dosage of
vemurafenib to patients with unresectable/metastatic BRAF mutated melanoma.
Secondary

 To characterize the overall safety and tolerability profile of SAR260301 administered as monotherapy (Part A) and in
combination with vemurafenib (Part B).

 To characterize the pharmacokinetic (PK) profile of SAR260301 administered as monotherapy (Part A) and in
combination with vemurafenib (Part B) as well as vemurafenib PK in combination with SAR260301 (Part B).

 To evaluate the food effect on SAR260301 PK (Part A).

 To assess preliminary antitumor activity according to Response Evaluation Criteria in Solid Tumors (RECIST)
Version 1.1.

 To assess the preliminary antitumor activity using volumetric computed tomography (CT) or magnetic resonance
imaging (MRI).

 To evaluate the pharmacodynamic (PD) effects of SAR260301 in the blood and tumor.

 To evaluate the PK/PD relationships.

 To identify the recommended Phase 2 dose (RP2D) of SAR260301 in combination with vemurafenib (Part B only).

 To assess the potential induction effect of SAR260301 on CYP3A (Part A).

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Exploratory

 To explore predictive markers of response. To evaluate pre-existing phosphatase and TENsin homologue (PTEN) status
in archival or fresh tumor samples and correlate PTEN deficiency with clinical outcome in subjects treated with
SAR260301.

 To evaluate other potential genetic alterations in the context of PTEN deficiency and correlate with clinical outcome.

 To explore the platelet function assay PFA100® as a potential useful point-of-care biomarker of PI3Kβ
(phosphoinositol-3-kinase beta) inhibition.
Methodology: This was an open-label, non-randomized, dose-escalation, safety, tolerability, PK and PD evaluation study of
SAR260301, given alone or in combination with vemurafenib, following a continuous daily schedule of 28-day cycles.
This study planned to initially include 2 parts (Part A and B):
Part A:

 Dose escalation study for the evaluation of the tolerability, safety, PK, and PD of SAR260301 administered as
monotherapy in patients with solid tumors or lymphomas, with enrichment for tumor types with a high expected rate of
PTEN deficiency.
Part B:

 Dose escalation study for the evaluation of the tolerability, safety, PK, and PD of SAR260301 administered in
combination with the approved dose of 960 mg BID of the BRAF inhibitor vemurafenib in patients with BRAF mutated
melanoma.

Initially, enrollment of the first cohort in the Part B combination phase was to start after the completion of DL2 in Part A for an
escalation in parallel thereafter. Following preliminary PK, the recruitment for Part B was put on hold until completion of dose
escalation in Part A, and the protocol was amended to allow for testing additional dose levels, and to adjust the dose according to
body surface area (BSA) to partly control exposure variability (Further details can be found in protocol Amendment 4 located in
Appendix 16.1.1).

Dose levels according to the latest protocol amendment are listed in the following table.
SAR260301 Dose Levels (DL) in Part A
SAR260301
DLa Up to Amendment 3 Amendment 4b
A-DL1 100 mg QD
A-DL2 100 mg BID
A-DL3 200 mg BID
A-DL4 400 mg BID
A-DL5 600 mg BID or 330 mg/m² BIDb
A-DL6 800 mg BID or 440 mg/m² BIDb
A-DL7 - 550 mg/m² BID
A-DL8 - 660 mg/m² BID
a Intermediate dose levels could be tested, after agreement between the Sponsor and investigators (Study Committee).
b Adjustment of dose according to body surface was implemented in new patients to be treated at the DL being tested at the time of
implementation of the Amendment 4. Further details can be found in protocol Amendment 4 located in Appendix 16.1.1.

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Dose escalation for Part A and B:
A Study Committee was set up, including at least the investigators, Sponsor team members (the Clinical Study Director, Global
Safety Officer, the Biostatistician and the Clinical Trial Operation Manager) and ad hoc experts (biomarkers, PK and statistic
representatives) when appropriate.
During Study Committee meetings, the committee decided on whether to escalate (or not) to the next dose level on the basis of
knowledge of the whole safety and tolerability profile, PK profile, and the Bayesian design recommendation (for details, refer to the
“Statistical Methods” section).
Although the dose-escalation process is guided by the safety evaluation during Cycle 1 of treatment, cumulative or irreversible
toxicities observed after subsequent administrations had to be considered also for the dose-escalation and dose-selection
decisions (ie, expansion of a given dose level, intermediate dose levels), upon recommendation from the Study Committee.
As a general definition, the MTD was defined as the highest dose with a tolerable global safety profile, controlling the risks of
overdose (true DLT rate above 35%) and the risks of unacceptable toxicity (true DLT rate above 60%). One MTD was to have
been assessed for the single agent (Part A) and another MTD was to have been assessed for the dose of SAR260301 in
combination with vemurafenib (Part B).
The dose escalation in Part A (SAR260301 monotherapy) and Part B (SAR260301 combined with vemurafenib) were to have
been stopped as soon as the determination of the doses not tolerated and/or MTDs.

The first dose level of SAR260301 that was planned to have been tested in the Part B combination study (B-DL1) was to have
been 2 dose levels below the MTD or the highest dose tested in Part A. The initial dose of vemurafenib to have been tested in
combination was to have been 720 mg BID, corresponding to 75% of the full dose for that drug. In dose level B-DL2, the
vemurafenib dosage was to have been increased to 960 mg BID, while SAR260301 was to have remained the same as that tested
in B-DL1. Once B-DL2 was found safe, the SAR260301 dose escalation in combination was to have been pursued.
Expansion cohort in Part A and B (to confirm the MTD):
Upon completion of the dose escalation phase, a preliminary RP2D (pRP2D) was to have been assessed by the Study Committee
for the expansion cohorts (in Part A and in Part B), primarily based on safety, tolerability and PK data. However, PK and PD
results could have supported the determination of the RP2D (especially in the case of situations where the MTD could not have
been determined in the absence of DLT at the maximal administrated dose). At the end of each escalation phase of both parts
(A and B), the pRP2D was to have been determined taking into account overall safety and tolerability occurring at all cycles (early
and late toxicities), PK, PD, PK/PD relationships, and antitumor activity.
In Part A (SAR260301 administered in monotherapy), 10 additional patients with PTEN deficient solid tumors or lymphomas were
planned to have been added at the pRP2D to further assess safety (especially any cumulative toxicity, which had to be taken into
account), antitumor activity, and PD.
In Part B (SAR260301 administered in combination with vemurafenib), it was planned to have 15 additional patients who were
PTEN deficient, BRAF mutated melanomas treated at this pRP2D for confirmation of safety (especially any cumulative toxicity,
which had to be taken into account), and evaluation of PK, PD, PK/PD, and antitumor activity. Determination of the RP2D in
combination was to have taken into consideration the same parameters as those used for determination of the SAR260301
pRP2D in monotherapy.

The study was terminated prematurely due to preliminary PK data indicating a rapid elimination associated with a nonsaturable
SAR260301 apparent clearance preventing the achievement of the minimum exposure required for a sustained PD effect.
Number of patients: Planned: approximately 75 (around 40 in Part A and 35 in Part B)
Treated: 21 (Part A only)
Evaluated:
Efficacy: 20
DLT assessment: 21
Safety: 21

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 Pharmacokinetics: 21
Diagnosis and criteria for inclusion:
Specific to Part A
Enrollment included patients with locally advanced or metastatic solid tumor disease as well as lymphoma for which no alternative
therapy was available.
Specific to Part B
Enrollment was planned to include patients with unresectable or metastatic BRAFV600 mutated melanoma confirmed using an
institutional validated assay in a CLIA-certified laboratory or a local Health Authority-approved assay:

 During the escalation phase: With or without prior exposure to vemurafenib or other BRAF inhibitor. Patients with only a
partial response to a BRAF inhibitor (<50% decrease in tumor volume by RECIST after 4 months of treatment) could
have been included.

 During the expansion phase: Patients who received ≤4 months of vemurafenib or other BRAF inhibitor, or prior regimen
combining a BRAF inhibitor with a MEK inhibitor, and who had either progressive disease, or <50% decrease in tumor
volume by RECIST after 4 months of treatment.

 Anterior scans pre-vemurafenib and on vemurafenib treatment had to be made available to the Sponsor or Sponsor
designated central imaging analysis.
Part A & Part B
Patients who were ≥18 years old and had at least 1 measurable lesion by RECIST Version 1.1; archived primary tumor biopsies or
surgical specimens, or biopsies of recurrence or metastasis (requested for all subjects for PTEN analyses and additional
molecular profiling); and at least 75 microns (preferably 125 microns) of formalin-fixed paraffin-embedded (FFPE) tissue or a
tissue block available for enrollment and for shipment to the Sponsor, or to a laboratory designated by the Sponsor (or sufficient
material for key evaluations based on Sponsor judgment).
PTEN status:

 During the escalation phases, inclusion was not restricted to, but was enriched for PTEN deficiency:
- Documented PTEN deficiency (loss of protein expression by immunohistochemistry [IHC] confirmed retrospectively
by Sponsor or a Sponsor-designated central laboratory). Tumor tissue was also used for assessment of PTEN
status via a variety of other assay platforms.
- Or, in Part A: Tumor types known to have a significant prevalence for PTEN deficiency including, but not restricted
to, KRAS wild-type colorectal, Cowden syndrome malignancies, endometrioid, melanoma (including BRAF wild
type in Part A), prostate, gastric, breast, lung, kidney, pancreas, liver, ovarian, squamous-cell carcinoma of the
head and neck, and thyroid.

 During the expansion phases, the patient had to have PTEN-deficient tumors as confirmed prospectively by loss of
protein expression via IHC on archival tumor tissue either locally or by the Sponsor or a Sponsor-designated central
laboratory.
Study treatments
Investigational medicinal product(s): SAR260301
Formulation: 100 mg film-coated tablets
Route(s) of administration: oral

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 Dose regimen: SAR260301 was administered at assigned dose levels QD or BID (~12 hours apart), within a 28-day cycle.
Patients were to have received all doses at a fasted condition (1 hour before breakfast and following an overnight fast in the
morning, and at least 2 hours after an afternoon snack and 1 hour before dinner, or 2 hours after dinner in the evening). For
patients participating in the food effect substudy, at a day convenient to the patient in Cycle 2, SAR260301 was to have been
taken within 30 minutes of a moderate-fat breakfast (fed condition). PK was characterized in the fed and fasted conditions.
This food effect evaluation was carried out in the escalation phase of Part A until 6 evaluable patients were included. On the
basis of the PK and safety findings, a recommendation was to have been made by the Study Committee to give all subsequent
doses for all patients in the study at all dose levels in the fed or fasted condition.
In Part B, SAR260301 was planned to be administered BID and concomitantly with vemurafenib.
Noninvestigational medicinal product(s): Vemurafenib (ZELBORAFTM)
Formulation: 240 mg film-coated tablets
Route(s) of administration: oral
Dose regimen: Vemurafenib was planned to be administered, but was not due to early study termination. Except at dose level
B-DL1, where vemurafenib was to have been administered at 720 mg BID during Cycle 1, it was planned to be administered at
the recommended dose of 960 mg (four 240 mg tablets) BID (~12 hours apart), within a 28-day cycle. Administration in relation
with food was to have depended on the recommendation previously made for SAR260301 administration. Dose reductions
were not to have gone below 480 mg BID.
Duration of treatment: SAR260301 was administered continuously in 28-day cycles. Unless toxicity requiring premature drug
discontinuation occurred during the first cycle, each patient had to receive at least 4 weeks of treatment.
Duration of observation: The duration of the study for an individual patient included a period to assess eligibility (screening
period) of up to 4 weeks (28 days), a treatment period of at least 1 cycle (28 days) of study treatment, and an end-of-treatment
visit at least 30 days (or until the patient receives another anticancer therapy, whichever was earlier) following the last
administration of study treatment. Treatment could have continued until precluded by toxicity, progression, death, or upon patient’s
request.
Criteria for evaluation:
Safety:
Primary endpoint
The primary safety endpoint was the incidence of DLTs at Cycle 1 (Day 1 to Day 28). A DLT was defined as any of the following
using the National Cancer Institute of Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 whether
related or not to the study treatment in the absence of clear evidence to the contrary, and if not related to a disease progression:

 ≥Grade 3 toxicities excluding:

- Grade 3 nausea and vomiting resolving to Grade ≤1 within 48 hours.
- Grade 3 diarrhea, if controlled with adequate anti-diarrheal therapy and lasting less than 48 hours.

 Other “non-gradable” toxicities:

- Cutaneous and non-cutaneous squamous-cell carcinoma, known to be related to vemurafenib, will not be
considered a DLT.
- If ≥25% (≥14 doses with twice daily dosing or ≥7 doses with once daily dosing) of SAR260301 (in Part A) or
SAR260301/vemurafenib (in Part B) were not administered during C1 due to toxicity.
- A treatment-emergent adverse event (TEAE), which in the opinion of the Study Committee, was of potential clinical
significance such that further dose escalation would have exposed patients to unacceptable risk.
If multiple toxicities were seen, the presence of DLT was based on the most severe toxicity experienced. At the end of each cycle,
each patient had to have been assessed by the Investigator as to whether or not the patient experienced DLT, and this information
had to have been recorded on the appropriate electronic case report forms (e-CRFs).

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Secondary endpoints
Secondary safety endpoints included the overall safety profile of SAR260301 administered in monotherapy (Part A) or in
combination with vemurafenib (Part B), and characterization in terms of the type, frequency, severity, timing, and relationship to
study therapy of any adverse events or abnormalities of physical findings, laboratory tests, vital signs, ECGs or LVEF
evaluations (ophthalmologic and dermatologic examinations in Part B); drug discontinuation due to adverse events; or serious
adverse events.
Pharmacokinetics: SAR260301 venous blood concentrations obtained after a once daily or twice daily regimen were used to
determine the following PK parameters on Day 1 and Day 28 of Cycle 1 in fasted conditions and on a selected day (Day X) of
Cycle 2 for food effect pilot study (moderate fat breakfast) using standard non-compartmental analysis: Cmax (maximum blood
concentration observed), tmax (time to reach Cmax), AUClast (area under the blood concentration versus time curve calculated using
the trapezoidal method from time zero to the real time corresponding to the last concentration above the limit of quantification),
AUCτ (area under the blood concentration versus time curve calculated using the trapezoidal method over the dosing interval),
Rac (AUCtau Day28/Day1), RacCmax (Cmax D28/Day 1), and CLss/F (apparent total body clearance at steady state after oral route);
t1/2z (apparent elimination half-life associated with the terminal slope) and the ratio of Cmax and AUCτ in fed (Cycle 2 Day X) versus
fasted (Cycle 1 Day 28) state were also calculated.
In the expansion phase of Part A, the plasma 4β-hydroxycholesterol on Day 15 versus Day 1 concentration ratios were to have
been calculated to evaluate the potential for CYP3A4 enzyme induction and inhibition by SAR260301 after repeated doses.
PK sampling times and assay methods: Venous blood samples (using dried blood spot technology [DBS]) were collected at Cycle
1 at 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24* (*QD regimen only) hours after the first daily administration on Day 1 and Day
28 and on a selected day of Cycle 2 for the food effect pilot study. Additional blood samples were collected before the first daily
dose (predose) on Day 2 (BID regimen), Day 8, Day 15, and Day 29 (corresponding to the Cycle 2 Day 1, BID regimen).
In addition DBS samples were collected by finger prick for investigation purposes at the following time points: predose (0), 2, and
6 hours after oral dosing of Cycle 1 Day 28 (not presented in this report).
Bioanalytical PK method: SAR260301 concentrations were determined in blood using a validated LC-MS/MS method with a lower
limit of quantification (LLOQ) of 1.00 ng/mL (Method DOH1109).
Pharmacodynamic biomarkers:
Blood (all patients) and tumor (expansion cohort only – optional) samples were obtained to document the PD effect of SAR260301
on the PI3K pathway. 8.5 mL blood samples were collected at various time points within Cycle 1 (predose on Day 1, 2, 15, and 28
and at 1 hour and 6 hours after SAR2060301 administration on Day 1 and 28) and processed to obtain platelet-rich plasma (PRP)
on which the level of pAKT inhibition was determined. On treatment tumor biopsies, planned to be done predose and during Cycle
1 Day 15 (±3 days) in the expansion phases, were not done.
Efficacy: Tumor response was to have been assessed using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
locally for all patients and was planned to be assessed centrally in the expansion cohort of Part B. Patients had to be assessed
using magnetic resonance imaging (MRI) or computerized tomography (CT) scan at least every 2 cycles, or less frequently, if
indicated. Responses had to be confirmed by repeat assessments performed at least 4 weeks after response criteria were first
met (RECIST, Version 1.1). International Workshop Group (IWG) response and revised criteria was planned to be used to assess
response in patients with lymphoma.
Exploratory endpoints
Predictive biomarkers:
The objective of this endpoint was to evaluate pre-existing PTEN status in archival or fresh tumor samples and correlate PTEN
deficiency with clinical outcome.

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Archival tumor sample: Archived primary tumor biopsies or surgical specimens, or biopsies of recurrence or metastasis, were
requested for all subjects for PTEN analyses and additional molecular profiling. At least 75 microns (preferably 125 microns) of
formalin-fixed paraffin-embedded (FFPE) tissue or a tissue block should have been available for enrollment and shipment to the
Sponsor, or a laboratory designated by the Sponsor. PTEN protein expression was tested using a validated immunohistochemistry
either locally or by Sponsor or laboratory designated by the Sponsor. For prospective enrolment in expansion phase, the validated
IHC was performed in a CLIA-certified laboratory. If less material was available, the patient could have still been eligible after
discussion with the Sponsor who assessed and confirmed that there was sufficient material for key evaluations.
Fresh tumor biopsy: Tumor sampling was not required for the escalation cohorts, but was mandatory at baseline for the expansion
cohorts.
The objective was to evaluate other potential genetic markers of response in the context of PTEN deficiency in tumor tissue and
whole blood.
Whole blood: One whole blood sample (10 mL) was collected during screening and processed for plasma circulating tumor DNA
genotyping for genetic alterations relevant to components of the PI3K and MAPK pathways, as well as other relevant signaling
pathways.
Other genetic markers could also have been assessed in archived and/or fresh tumor tissue samples when sufficient material was
available.
Optional genotyping or pharmacogenetics:
One optional blood sample was collected on Day-1 (predose) to investigate allelic variants of drug metabolism enzymes and/or
drug transporters as intrinsic factors associated with PK or PD variability of SAR260301.
Evaluation of platelet function: The impact of the PI3K pathway modulation in platelet on platelet function was done using the
point-of-care assay PFA100® by the measure of closure time using both a collagen/epinephrine cartridge and a P2Y PGE1/ADP
cartridge. For that purpose, 2.7 mL whole blood samplings were drawn predose on Days 1, 2, 15, and 28, and 1 and 3 or 6 hours
postdose on Days 1 and 28 and 24 hours predose on Day 28.
Statistical methods:
Determination of sample size:
This study aimed to establish the MTD of SAR260301 according to DLTs observed and the RP2D of SAR260301 to be
administered:

 as a single agent,

 in combination with the approved dose of the BRAF inhibitor, vemurafenib 960 mg BID, in patients with BRAF mutated
melanoma.
Based on different simulated scenarios (1000 simulated trials on 8 different scenarios), it was anticipated that almost likely around
25 to 30 safety-evaluable patients would be enrolled in Part A and 15 to 20 safety evaluable patients in Part B during the
escalation phase of the study. The actual sample size could have varied depending on the DLTs observed and number of dose
levels actually explored.
In order to complete the assessment of the global safety profile at the MTD, approximately 10 patients had to be enrolled in the
dose expansion cohort of Part A and approximately 15 patients in the dose expansion cohort of Part B. If 3 clinical objective
responses (or less) were observed among 15 patients in the Part B expansion, a response rate of 40% would be ruled out with
less than 10% (precisely, 9.1%) chance to falsely rejecting the drug.
A total of approximately 75 patients were to have been enrolled in the study.
Analysis populations:
Safety population: all patients who received at least 1 dose of study treatment.

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Patients evaluable for DLT evaluation: patients who had received a complete first cycle with at least 75% dosing unless the patient
was discontinued early during Cycle 1 due to a DLT.
Efficacy population: patients who had received at least 1 cycle of study treatment, and provided a baseline and at least 1 post
baseline tumor assessment. Patients with early progression as per RECIST 1.1 were also included in this population.
Adaptive Bayesian design providing recommendation on SAR260301 dose escalation:
An adaptive Bayesian design with overdose control was used to provide dose recommendations on SAR260301 dose escalation.
This adaptive dose escalation was based on a statistical (2-parameter logistic) model for the probability of dose-limiting toxicity
(DLT) in the whole population as a function of dose. The model was used to estimate whether the probability of DLT (also called
DLT rate) at each candidate dose level was within a targeted interval of 16% to 33% after each new cohort of DLT evaluable
patients.
Dose escalation was indicated by the design if the probability of DLT within the targeted interval at the next level was greater than
at the current level or de-escalation if the probability of DLT within the targeted interval at a lower level was greater than at the
current level. Otherwise, subsequent patients were treated at the current dose level. Intrapatient dose escalation was not allowed.
Intrapatient dose escalation for vemurafenib was to have been allowed only within the initial combination dose level B-DL1, where
vemurafenib 720 mg BID could have been increased to 960 mg BID if no DLT had occurred in Cycle 1.
In addition, escalation occurred when the overdosing and unacceptable toxicity risks were controlled at the levels of 25% and 5%,
respectively. That is to say, the risks of a DLT rate above 33% and above 60% could not have exceeded pre-specified tolerated
risk levels of 25% and 5%, respectively. To further increase the safety of dose escalation, the maximum increase in dose from
1 level to the next was 100%. In addition, if 2 or more patients in the current cohort had a Grade 2 related SAR260301 toxicity or if
any patient had a DLT, then the maximum increase in dose from 1 level to the next was to have been no greater than 50%.
Enrollment at the next dose level could have proceeded only if a minimum of 3 patients completed treatment without a DLT at the
current dose level for at least the duration of 28 days (1 cycle).
Only DLTs reported during Cycle 1 have been considered in the modeling.
Safety analyses:
Safety endpoints included:

 DLTs,

 Treatment-emergent AEs (TEAEs), including serious adverse events (SAEs),

 Deaths,

 Laboratory assessments,

 Vital signs,

 Electrocardiograms.
All safety analyses were descriptive and performed on the safety population by actual dose level.
Dose-limiting toxicities occurring during Cycle 1 were provided by dose level, with details provided by patient. Moreover, AEs
meeting DLT criteria and occurring after Cycle 1 were also listed.
The primary focus of AE reporting was TEAEs, defined as any AEs that occurred or worsened during the on-treatment period (ie,
from the first administration of study treatment up to 30 days after the last dose). Treatment-emergent AEs were coded using
MedDRA Version 17.1, with intensity graded by the National Cancer Institute (NCI) Common Toxicity Criteria Adverse Event
(CTCAE) Version 4.03. Adverse event incidence tables presented the number and percentage of patients by primary system
organ class (SOC) and preferred term (PT) and sorted by SOC internationally agreed order.

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Summaries of all TEAEs, related TEAEs, treatment-emergent SAEs, TEAEs leading to treatment discontinuation, TEAEs leading
to dose modification (delay, reduction, omission), and TEAEs leading to dose interruption were provided. Worst grades were
summarized. Some AE tables presenting data by high level group term (HLGT), high level term (HLT), and PT were also
presented.
Clinical laboratory values were converted to standard international units by data management, then were graded according to the
NCI-CTCAE version 4.03 whenever applicable, using laboratory ranges provided by the laboratory analyzing the sample whenever
possible and using generic normal ranges for other parameters. The maximum grade (worst) per patient was summarized. When
the NCI-CTCAE was not applicable, laboratory values “out of normal ranges” were summarized.
Vital sign data were not described.
Left ventricular ejection fraction (LVEF) data were listed.
Efficacy analyses:
The endpoint was ORR (CR + PR), which was summarized by dose level.
Due to the early termination of the study, all analyses planned in the protocol were not performed.

Summary: This study was planned to include 2 parts (Part A and B), of which the second part (Part B) was never initiated due to
the unfavorable PK properties of SAR260301; therefore, only results from Part A are presented in this synoptic report.
Population characteristics:
Twenty-one patients were enrolled and treated as follows:

 3 in the A-DL1 (100 mg QD) cohort;

 3 in the A-DL2 (100 mg BID) cohort;

 3 in the A-DL3 (200 mg BID) cohort;

 6 in the A-DL4 (400 mg BID) cohort;

 4 in the A-DL5 (600 mg BID ) cohort;

 2 in the A-DL6 (440 mg/m2 BID) cohort.

Of those 21 patients, 19 discontinued due to disease progression and 2 discontinued due to other reasons (ie, “physician and
patient decision” for 1 patient and “patient decision” for 1 patient).
All 21 patients were included in the treated population and were evaluable for DLTs. Twenty patients were included in the
efficacy evaluable population; 1 patient in the A-DL5 cohort was not evaluable for efficacy since her radiological tumor
assessment was performed in an outside facility, albeit disease progression was based on evidence of symptomatic
deterioration.
The primary tumor sites (for >1 patient) at initial diagnosis were the colon/rectum (7 patients), skin (3 patients), breast and
ovary (2 patients each); and the most common histology types (>1 patient) were adenocarcinoma (12 patients) and melanoma
(3 patients). No patients with lymphoma were enrolled. All patients had metastatic disease. Most patients had Stage IV
(11 patients) or Stage III cancer (5 patients) at initial diagnosis. Median time from initial diagnosis and date of first study
treatment dose for all patients was 4.50 years (range: 1.3 to 22.2 years). Most patients (19) had ≥2 organs involved at
baseline, with the most commons organs (for >10 patients) identified as the lungs (16 patients), lymph nodes (12 patients), and
liver (11 patients). The median number of prior lines of anticancer treatment regimen was 4 (ranging from 1 to 9). Eighteen
patients had prior cancer surgery, and 9 patients had prior radiotherapy.

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 Some level of tumor molecular characterization was available for 15 of the 21 treated patients at study entry. Genetic
alterations had been documented in 8 of these 15 patients and involved the following genes: PTEN (1 patient), PIK3CA (4
patients), EGFR (1 patient), NRAS (2 patients), KRAS (3 patients), TP53 (3 patients), BRCA2 (1 patient), ATM (1 patient), and
APC (1 patient). Three patients had PTEN-null disease documented at the level of PTEN protein expression by the study site.
Grade 3-4 laboratory abnormalities at baseline included Grade 3 lymphopenia (2 patients) and Grade 3 GGT increased
(2 patients).
Safety results:
Exposure
The median number of days on treatment was 36.0 for the A-DL1; 30.0 for the A-DL2; 28.0 for the A-DL3; 56.0 for the A-DL4;
28.0 for the A-DL5; and 109.5 for the A-DL6 cohort. Most patients received between 1 cycle (8 patients) and 2 cycles (9
patients) of treatment. Two patients received at least 6 cycles. Median relative dose intensity (RDI) was 0.97 for the A-DL1;
0.85 for the A-DL2; 1.04 for the A-DL3; 0.54 for the A-DL4; 0.76 for the A-DL5; and 0.94 for the A-DL6 cohort.
Based on the exposure dataset, 9 patients had dose administration as planned and 12 patients had at least 1 dose omission.
No patient had a cycle delayed.
Dose-Limiting Toxicities
Two DLTs occurred during dose escalation:

 Grade 3 pneumonitis: 1 patient treated at A-DL4 (400 mg BID), was discontinued from the study after completion of
Cycle 1 for disease progression. Grade 1 pneumonitis was incidentally documented on CT scan. The event worsened
from Grade 1 to Grade 3 seventeen days after the last SAR260301 administration. No other cause could be
incriminated. The event resolved with corticosteroids. Further details can be found in the patient’s safety narrative in
Section 15.3.

 Grade 3 GGT increased: 1 patient treated at A-DL5 (600 mg BID), was discontinued from the study midway through
Cycle 1 for disease progression, at which time, Grade 3 GGT increased was documented in the context of liver
metastases (Grade 1 at baseline). Grade 3 GGT increased resolved promptly after discontinuation of SAR260301 and in
the absence of initiation of another anticancer treatment. The event was retrospectively attributed to study treatment.
Further details can be found in the “Treatment-Emergent Adverse Events” section.
Treatment-Emergent Adverse Events
All 21 patients had at least 1 TEAE (all grades), of which 13 had treatment-related TEAEs. Nine patients had at least
1 ≥Grade 3 TEAE, of which 2 had treatment-related ≥Grade 3 TEAEs (1 pneumonitis and 1 GGT increased).
The most common TEAEs (reported by ≥3 patients) in all cohorts (all grades), regardless of relationship to treatment, were
fatigue (11 patients); nausea (6 patients); diarrhea and abdominal pain (5 patients each); cough and vomiting (4 patients each);
decreased appetite, headache, constipation, myalgia, back pain, and GGT increased (3 patients each). Five infectious events
were documented: urinary tract infection (1 patient), pneumonia (1 patient), viral infection (1 patient), mucosal infection (1
patient), and upper respiratory tract infection (1 patient). Three bleeding events were documented: hemorrhoids (1 patient),
vaginal hemorrhage (1 patient), and pulmonary hemorrhage (1 patient). The only ≥Grade 3 TEAEs reported by more than
1 patient were GGT increased (3 patients, of which 1 had a treatment-related TEAE [Grade 3 GGT increased DLT]); pleural
effusion and disease progression (2 patients each).
Nine patients had at least 1 treatment-emergent SAE, of which 1 patient had a treatment-related SAE (Grade 3 pneumonitis
DLT). Treatment-emergent SAEs included the following: pleural effusion, abdominal pain, and disease progression (2 patients
each); autoimmune disorder, hypercalcemia, confusional state, syncope, pneumonitis, pulmonary hemorrhage, upper
abdominal pain, and bile duct obstruction (1 patient each). Further details on these patients can be found in the patients’ safety
narratives in Section 15.3.

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 Two patients (1 in the A-DL1 cohort and 1 in the A-DL5 cohort) died as the result of a treatment-emergent SAE that was
unrelated to study treatment (disease progression) within 30 days of the last study treatment dose. Further details on these
patients can be found in the patients’ safety narratives in Section 15.3. An additional patient in the A-DL2 cohort died due to
disease progression post-study, 77 days after the last study treatment dose.
No patient had a TEAE that led to permanent discontinuation or dose modification of study treatment.
Based on the AE dataset, 6 patients had at least 1 TEAE (all grades) leading to dose interruption as follows:

 A patient in the A-DL1 cohort, presented with recurrent pleural effusion due to malignant disease. Study treatment was
interrupted for insertion of a chest tube, but was never reinitiated due to disease progression.

 A patient in the A-DL2 cohort, had intermittent abdominal pain at baseline in the context of liver metastases. Study
treatment was interrupted at the end of Cycle 1 for worsening gastrointestinal symptoms and Grade 3 GGT increase
consistent with progression of liver metastases, which was retrospectively confirmed.

 A patient in the A-DL2 cohort, presented with syncope on Cycle 1 Day 1, 1 to 2 hours after the evening dose of study
treatment. Study treatment was interrupted and quickly resumed after establishing a diagnosis of post-tussive syncope
due to the pneumonia. Furthermore, the patient had study treatment interrupted at the end of Cycle 5 because of
increased uric acid in the context of persisting diarrhea related to malignant disease (Good’s syndrome - autoimmune
process related to thymic carcinoma). Uric acid was quickly normalized following hydration and allopurinol, but study
treatment was never reinitiated due to evidence of progressive disease.

 A patient in the A-DL5 cohort, presented with Grade 2 dehydration (unrelated to study treatment) on Day 15 of Cycle 1
for which the study treatment was interrupted (1 dose omission) but resumed on the same day. There was a slight drop
in the patient’s hemoglobin at 85 g/L from 91 g/L at baseline (Grade 2). The patient was rehydrated with normal saline
and received a transfusion with red blood cells. The event of dehydration resolved on the same day. The patient’s
hemoglobin stabilized at 101 g/L (Grade 1) at the end of Cycle 1.

 A patient in the A-DL5 cohort, had study treatment interrupted midway through Cycle 1 for headache and Grade 3 GGT
increased (Grade 1 at baseline). The patient was found to have new punctate brain lesions and an increase in size of
liver lesions. The patient was discontinued from the study for disease progression, and Grade 3 GGT increased
recovered promptly after discontinuation of SAR260301 and in the absence of initiation of another anticancer treatment.
GGT increase was retrospectively attributed to study treatment and was considered to be a DLT.

 A Patient in the A-DL6 cohort, midway through Cycle 2, had vomiting, fever and increased transaminases (Grade 3)
found later to be due to obstruction of a biliary stent due to disease progression. The event resolved with replacement of
the stent.
Laboratory Results
Overall, there were no relevant laboratory abnormalities.
The only ≥Grade 3 hematologic abnormalities were 3 cases of lymphopenia (all Grade 3). For all of these patients,
lymphopenia was present at baseline (Grade 3 in 1 patient and Grade 2 in 2 patients), and there was no clear evidence of
worsening while on treatment.
≥Grade 3 chemistry abnormalities included:

 5 patients with ≥Grade 3 GGT increased, of which only 1 patient had an increase related to SAR260301 (DLT); all
others had an increase related to the underlying malignant disease.

 2 patients with ≥Grade 3 ALT increased, of which 1 patient also had concomitant Grade 3 AST increased; all were
related to the underlying malignant disease.

 1 patient with Grade 3 hypokalemia (concomitant to Grade 3 decrease in bicarbonate and increased uric acid) occurring
20 days after the last administration of SAR260301. The patient was discontinued from the study due to progressive
disease, in the context of thymoma-associated autoimmune enteropathy.

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 One patient, with metastatic hepatocellular carcinoma with bone involvement, had serious Grade 2 hypercalcemia, which was
considered to be related to disease progression.
No patient had a ≥Grade 3 coagulation abnormality during the study.
Other safety results:
Thyroid function
Overall, a small number of patients had at least 1 non-gradable thyroid function abnormality as follows:

 4 patients (2 in the A-DL4 and 2 in the A-DL5 cohort) had thyroid stimulating hormone (TSH) >ULN during the
on-treatment period; 2 had above normal TSH present at baseline. One patient with increased TSH at baseline and at
Cycle 2 also had <LLN free thyroxine 4 (FT4) levels at baseline and on treatment.
Cardiac function
No drop in LVEF was documented.
Pharmacokinetic results:
Pharmacokinetic parameters were obtained in 21 patients during Cycle 1 Day 1 and 15 patients during Cycle 1 Day 28. During
Cycle 1 Day 1, 1 patient was not excluded from the PK analysis despite having a single episode of vomiting (approximately 40
minutes after oral dosing) since there was no evidence of pill presence in the vomit and the PK parameters of SAR260301
(Cmax and AUCτ) were in the range of those observed in the same dose level for the other patients.
Among the 7 patients treated during Cycle 2 in fed conditions (moderate fat breakfast), 6 patients were evaluable for the
optional pilot food effect study part. One patient was excluded due to a protocol deviation (SAR260301 oral dosing was taken
1.8 hours after moderate fat breakfast instead of within 30 minutes, as per protocol).
Mean PK profiles of SAR260301 concentrations in blood at Day 1 and Day 28 in fasted conditions are presented in Figure 1
and Figure 2, respectively. Mean PK profiles of SAR260301 concentrations in blood in fed conditions are presented in Figure 3.
In fasted conditions, mean PK parameters of SAR260301 in blood at Day 1 and 28 are presented in Table 1 and Table 2,
respectively; PK parameters as a function of dose are illustrated in Figure 4 and Figure 5; the accumulation ratios on Cmax and
AUCτ (Day 28/Day 1) are presented in Table 3; PK parameters of SAR260301 in blood in fed conditions are presented in Table
4; and the pilot food-effect study results are presented in Table 5.

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Figure 1 - Mean concentration-time course of SAR260301 after oral administration of SAR260301 during Cycle 1 – DAY 1 (fasted)
SAR260301 - DAY 1 100 mg bid
100 mg qd
200 mg bid
5000 400 mg bid
Mean (SD) SAR260301 Concentration (ng/mL) 600 mg bid
800 mg (440 mg/m²) bid
LOQ = 1 ng/mL
4000

3000

2000

1000

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (h)

SAR260301 - DAY 1

100 mg bid
10000 100 mg qd
200 mg bid
Mean SAR260301 Concentration (ng/mL)

400 mg bid
600 mg bid
1000 800 mg (440 mg/m²) bid
LOQ = 1 ng/mL

100

10

0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (h)

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 Figure 2 - Mean concentration-time course of SAR260301 after oral administration of SAR260301 during Cycle 1 – DAY 28
(fasted)

SAR260301 - DAY 28

4000 100 mg bid

Mean (SD) Blood SAR260301 Concentration (ng/mL) 100 mg qd
200 mg bid
400 mg bid
600 mg bid
3000 800 mg (440 mg/m²) bid
LOQ = 1 (ng/ml)

2000

1000

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (h)

SAR260301 - DAY 28 100 mg bid

100 mg qd
10000 200 mg bid
Mean Blood SAR260301 Concentration (ng/mL)

400 mg bid
600 mg bid
1000 800 mg (440 mg/m²) bid
LOQ = 1 (ng/mL)

100

10

0.1

0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (h)

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Figure 3 - Mean concentration-time course of SAR260301 after oral administration of SAR260301 on fed conditions during Cycle 2

SAR260301- CYCLE 2 - FED 100 mg bid Day 1

800 100 mg qd Day 1
400 mg bid Day 1

Mean (SD) SAR260301 Concentration (ng/ml)

LOQ = 1 (ng/ml)

600

400

200

0
0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (hr)

100 mg bid Day 1

SAR260301 - CYCLE 2 - FED
100 mg qd Day 1
1000
400 mg bid Day 1
LOQ = 1 (ng/mL)
Mean SAR260301 Concentration (ng/mL)

100

10

0 2 4 6 8 10 12 14 16 18 20 22 24
Nominal Time (h)

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 Table 1 - Summary of SAR260301 PK parameters in blood following oral administration of SAR260301 on Day 1

Mean ± SD Dried Blood SAR260301 – DAY 1

(Geometric Mean) [CV%] 100 mg QD 100 mg BID 200 mg BID 400 mg BID 600 mg BID 800 mg BID (440 mg/m2 BID)b
N 3 3 3 6 4 2
Cmax 322 ± 93.2 424 ± 145 825 ± 961 1570 ± 908 1540 ± 487 4660 ± NC
(ng/mL) (312) [29] (405) [34] (465) [116] (1330) [58] (1480) [32] (3080) [NC]

tmaxa 1.5 0.5 0.58 1.15 0.78 1.24

(h) (0.50 - 1.50) (0.50 - 0.55) (0.48 - 1.50) (0.50 - 2.02) (0.42 - 2.00) (0.48 - 2.00)
AUClast 730 ± 192 539 ± 105 1190 ± 929 2440 ± 909 3810 ± 1490 6840 ± NC
(ng•h/mL) (713) [26] (531) [20] (957) [78] (2300) [37] (3610) [39] (6220) [NC]
AUC0-12 694 ± 230 541 ± 105 1200 ± 928 2460 ± 914 3840 ± 1480 6880 ± NC
(ng•h/mL) (668) [33] (534) [19] (961) [77] (2320) [37] (3650) [38] (6260) [NC]
AUC0-24 734 ± 199
NA NA NA NA NA
(ng•h/mL) (716) [27]
t1/2z 5.19 ± 2.44
NA NA NA NA NA
(h) (4.71) [47]
SD: standard deviation; CV: coefficient of variation; QD: daily; BID: twice daily; NC: not calculated; NA: not applicable
a Median (Min - Max)
b According to their body surface area, 1 patient received 700 mg BID and the other received1000 mg BID

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 Table 2 - Summary of SAR260301 PK parameters in blood following repeated oral administration of SAR260301 on Day 28

Mean ± SD Dried Blood SAR260301 – DAY 28

(Geometric Mean) 100 mg 200 mg 800 mg BID
[CV%] 100 mg QD 400 mg BID 600 mg BID
BID BID (440 mg/m2 BID)b
N 2 2 1 5 3 2
1240 ±
Cmax 344 ± NC 445 ± NC 228 ± NC 2700 ± 859 3870 ± NC
535
(ng/mL) (296) [NC] (441) [NC] (228) [NC] (1140) [43] (2620) [32] (3860) [NC]

tmaxa 0.78 0.77 1.5 1.03 0.5 1.24

(0.55 -
(h) (0.52 - 1.02) (1.50 - 1.50) (0.50 - 2.13) (0.47 - 0.55) (0.95 - 1.52)
1.00)
2650 ±
AUClast 618 ± NC 647 ± NC 589 ± NC 4940 ± 2510 7130 ± NC
990
(ng•hr/ml) (600) [NC] (640) [NC] (589) [NC] (2500) [37] (4560) [51] (7030) [NC]
AUCτ 617 ± NC 700 ± NC 589 ± NC 2730 ± 1010 5050 ± 2620 7180 ± NC
(ng•hr/ml) (599) [NC] (685) [NC] (589) [NC] (2580) [37] (4640) [52] (7080) [NC]
CLss/F 172 ± NC 149 ± NC 339 ± NC 164 ± 61.4 139 ± 59.7 125 ± NC
(L/h) (167) [NC] (146) [NC] (339) [NC] (155) [37] (129) [43] (118) [NC]
t1/2z 7.59 ± NC
NA NA NA NA NA
(h) (7.59) [NC]
SD: standard deviation; CV: coefficient of variation; QD: daily; BID: twice daily; NC: not calculated; NA: not applicable
a Median (Min - Max)
b According to their body surface area, 1 patient received 700 mg BID and the other received1000 mg BID

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 Figure 4 - CLss/F over the dose range tested

SAR260301 - DAY 28
400 Individual values
Mean (SD) values

300
CLss/F (L/h)

200

100

0
100 200 400 600 700 800 1000
Dose (mg)

SAR260301 maximal concentrations were rapidly reached with tmax ranging from 0.5 to 1.5 hours post oral dosing, either on Day 1
and Day 28 (Table 1 and Table 2). Then concentrations decreased rapidly up to the last sampling time, 24 hours for QD or
12 hours for BID regimens (Figure 1 and Figure 2).
Overall, a moderate to high variability was observed for Cmax with CV ranging from 29 % to 116%. A low to high variability was
observed for AUCτ (CV ranging from 20 to 77%).
Based on mean values, the apparent total body clearance at steady state (CLss/F) remained almost constant over the dose range
tested (100 mg BID to 800 mg BID) after repeated oral BID administration. Overall, CLss/F was 165 L/h (CV=42%).
After a single daily dose of 100 mg QD, the mean apparent elimination half-life was 5.2 hours.

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 Figure 5 - SAR260301 PK parameters (AUCτ) as a function of dose on Day 1 and Day 28 during Cycle 1

12000 SAR260301 - DAY 1 Individual values

Mean (SD) values

10000
AUC0-12 (ng•h/mL)

8000

6000

4000

2000

0
100 200 400 600 700 800 1000
Dose (mg)

SAR260301- DAY 28
10000 Individual values
Mean (SD) values

8000
AUC (ng•hr/mL)

6000

4000

2000

0
100 200 400 600 700 800 1000
Dose (mg)

Based on mean values, exposure increased almost in proportion to the increase of dose, over the dose range 100 mg BID to
800 mg BID (440 mg/m² BID). For an 8-fold increase in dose, Cmax and AUCτ increased by 11- and 13-fold, respectively, on Day 1
and by 9- and 10-fold on Day 28.

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 Table 3 - Accumulation ratio D28/D1: Geometric mean value by dose levels
Raccmax Rac
Treatment
N D28/D1 Cmax ratio D28/D1 AUCτ ratio
100 mg QD 2 1.00 0.840
100 mg BID 2 1.20 1.32
200 mg BID 1 1.90 1.39
400 mg BID 5 1.02 1.18
600 mg BID 3 1.64 1.23
800 mg BID (440 mg/m2 BID) 2 1.26 1.13
Overall (BID regimen only) 13 1.26 1.22

QD: daily; BID: twice daily

The PK of SAR260301 was similar between Day 1 and Day 28; no accumulation was observed during Cycle 1 between Day 1
and Day 28 (overall, 1.22-fold increase of AUCτ).
Table 4 - Summary of SAR260301 PK parameters in blood following repeated oral administration of SAR260301 in fed conditions
during Cycle 2
Mean ± SD Blood SAR260301 PK parameters – fed conditions
(Geometric Mean) [CV%] 100 mg QD 100 mg BID 400 mg BID
N 1 1 4

Cmax 89.4 ± NC 166 ± NC 503 ± 265

(ng/mL) (89.4) [NC] (166) [NC] (456) [53]
tmax a 3.00 1.88 2.53
(h) (3.00 - 3.00) (1.88 - 1.88) (1.42 - 3.10)
AUClast 370 ± NC 438 ± NC 1990 ± 770
(ng•h/mL) (370) [NC] (438) [NC] (1890) [39]
AUCτ 375 ± NC 443 ± NC 2030 ± 814
(ng•h/mL) (375) [NC] (443) [NC] (1920) [40]
SD: standard deviation; CV: coefficient of variation; QD: daily; BID: twice daily; NC: not calculated
a Median (Min - Max)
Table 5 - Food effect pilot study – fed over fasted conditions (geometric mean)
FASTED - C1D28 FED - C2Dx Ratio Fed/Fasted

Treatment N Cpredose/Cmax (%) Cpredose/Cmax (%) Cmax AUCτ

100 mg QD 1 0.929 1.50 0.529 0.801

100 mg BID 1 1.27 2.20 0.428 0.797
400 mg BID 4 2.53 9.23 0.430 0.787
Geometric mean 6 NA NA 0.444 0.791
QD: daily; BID: twice daily; NA: not applicable
Patient 840002008 was excluded from the food-effect study.
After a moderate fat breakfast, a negative food effect was observed. Median tmax was slightly delayed when compared to fasted
conditions (Cycle 1 Day 28). Cmax and AUCτ decreased respectively, by 56% and 21%, when compared to fasted conditions.

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 Biomarker results:
Secondary PD objective:

 Near complete (≥80%) and sustained (≥6 hours) pathway inhibition was observed in only 2 patients (1 from the A-DL5
cohort and one from the A-DL6 cohort). For both patients, Cmax read over 10µM, consistent with the SAR260301 total
drug concentration threshold required to induce significant pathway inhibition as predicted from nonclinical studies. The
results indicated collectively that pharmacologically active concentrations are reached and mechanistic proof-of-concept
is clinically established. Pharmacodynamic data are provided in the Pharmacodynamic Biomarker Analysis Report.

 A preliminary PK/PD analysis indicates that maximum inhibition of phosphor-AKT/total AKT significantly correlated with
exposure parameters on Day 28. According to regression lines, the thresholds to reach 60% and 80% inhibition on Cmax
were respectively 7µM and 11µM, and the threshold to reach 60% and 80% inhibition on AUC0-12 were 12 µM.h and
20 µM.h, respectively. The results of this PK/PD analysis are preliminary and may be part of a separate report at a later
date.
Exploratory objectives:

 For all 21 treated patients, archival tumor tissue samples were available for retrospective documentation of PTEN
expression. Tumor sample for 1 patient was nonevaluable. The 3 PTEN-null cases were confirmed by central testing. All
remaining cases expressed PTEN. Data will be provided in a separate translational medicine report at a later date.

 The impact of SAR260301 on platelet function using the point-of-care PFA100® assay was assessed from A-DL4.
Although inconsistent, there was a trend for closure time prolongation ≥1.3 compared to baseline with Cmax ≥6µM.
These data are preliminary and may be part of a separate translational medicine report at a later date.
Efficacy results:
Twenty patients were evaluable for tumor response by RECIST Version 1.1. No patient had confirmed CR or PR, and most
patients progressed quickly after completion of the first or second cycle. Five patients had stable disease (1 PTEN-null heavily
pretreated patient with colorectal cancer at A-DL6 showed stable disease lasting for 6 months), 14 patients had progressive
disease, and 1 patient was not evaluable.
Issue date: 13-Jan-2016

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